Research has been carried out in three main areas: Effect of parenchymal liver disease on the metabolism of therapeutic agents. Since sedatives and analgesics are commonly used in patients with parenchymal liver disease (especially of alcoholic etiology), we assessed the effect of such dysfunction on the disposition of Valium(R), Demerol(R), and phenobarbital. The half life of all three drugs was prolonged significantly in patients with cirrhosis and in individuals with acute viral hepatitis for the first two drugs. This impairment was major (twofold) for Valium and Demerol and modest (40%) with phenobarbital which partly bypasses hepatic metabolism and is excreted (30%) unchanged in urine. Our data suggest that this impairment of drug elimination with liver disease is primarily due to deranged metabolism of these agents in the diseased liver. Future studies are aimed at elucidating the effects of liver disease on the elimination of other commonly used sedatives such as paraldehyde, Librium(R) and oxazepam. It is our hope to discover the optimal sedative (one whose elimination is not abnormal) for such patients. Transport of thiamine hydrochloride via normal gut and the effects of alcohol and folate deficiency on this. We have shown that thiamine is absorbed via the rat intestine by a dual process -- active for low (less than 2 micron M) and probably physiological concentrations and passive for the higher concentrations of the vitamin. Alcohol and folate deficiency both independently inhibit active, but not passive, transport of the thiamine. Future studies are planned to elucidate the mechanism(s) of this effect. Cerebral DNA and RNA synthesis in thiamine deficiency. We have shown a major impairment of regional cerebral DNA synthesis in vivo in thiamine deficient rats. This effect was progressive with thiamine depletion, was very substantial at the height of the deficiency, was rapidly reversible following administration of thiamine and affected only a small pool of DNA (since net total DNA levels remained normal).